Synthetic chemistry has provided access to a wide class of peptides and proteins which was out of bound several decades ago, particularly peptides containing more than 10-15 amino acids. With the advent of solid phase peptide synthesis (SPPS), peptides longer than 20 amino acids could be readily built on a solid support through either Boc/Bzl or Fmoc/<i>t</i>-Bu strategies. However, it was still challenging to synthesize peptides containing 50 or more amino acids by the linear SPPS because of lower yields and reduced purities with increasing peptide length. Thus, the convergent hybrid strategy becomes highly attractive wherein high purity peptide fragments can be coupled together in solution phase to overcome the drawbacks of the linear SPPS. Some of the shortcomings of this strategy are the need for tight control over epimerization because of the limited non-epimerizable coupling junctions, and the decreasing solubility of the growing protected peptide chain in organic solvents. The introduction of native chemical ligation (NCL) in 1994 has helped immensely in the synthesis of numerous large peptides and proteins, which were inaccessible earlier. Retatrutide, a 39-amino acid synthetic peptide, is a once-weekly novel GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like-peptide-1) and glucagon receptor agonist and is currently in phase 2 clinical trials for diabetes and obesity. Herein, we have developed an NCL synthesis where two unprotected peptide fragments are coupled in aqueous media without any epimerization to yield retatrutide cysteine analogue, which is then subjected to desulfurization with water soluble radical initiators to chemoselectively give retatrutide. The NCL strategy is potentially the greenest of all hybrid approaches to produce a synthetic peptide.

Synthesis of retatrutide by native chemical ligation (NCL), a once-weekly GIP, GLP-1, and glucagon receptor triagonist

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